14β,15β-methylene-17α-hydroxymethyl-androgens

ABSTRACT

The disclosed invention relates to the unexpected finding of novel steroids which are characterized by a 14beta,15beta-cyclopropane ring and a 17alpha hydroxymethyl group. These steroids according to the invention are found to have in common an androgenic activity. They can be used for the preparation of an agent for male contraception, as well as for the preparation of a medicament for the treatment of androgen insufficiency.

This application is a 371 of PCT/EP00/12009 filed Nov. 29, 2000.

The present invention is in the field of steroid compounds having acyclopropane ring, which ring includes carbon atoms 14 and 15 of thesteroid skeleton. More particularly, the invention pertains to suchsteroid compounds as possess an androgenic activity.

Steroids having the above-indicated cyclopropane ring have beendisclosed in EP 768 316, which is in the field of female contraceptionand hormone-therapy against endometriosis or climacteric complaints. Thesteroids are described as having progestagenic activity, examples being14α,15α-methylene estra-4,9-diene-3-one-17α-ol and 3-oxo14β,15β-methylene estra-4,9-diene-17β-yl (N-phenyl)carbamate. Neitherpotency, nor any other receptor activities, of these progestagens can bederived from this disclosure.

In a non-prepublished patent application PCT/DE99/01795 (published onDec. 29, 1999 as WO 99/67276) a group of 14,15-cyclopropyl steroids hasbeen described, among which are 17β-hydroxy substituted ones.

Another non-prepublished patent application is WO 00/53619 wherein agroup of androgenic steroids is described which have a 14β,17αconfiguration, viz. (14β,17α)-17-(hydroxymethyl) steroids.

The present invention now provides a novel group of steroids of thegeneral type as indicated above, which possess an unexpected androgenicactivity. Distinct from the progestagens disclosed in the art, theandrogens of the present invention—including very potent ones—int.al.satisfy the requirements that the cyclopropane ring is β-oriented andthat on carbon atom no. 17 a hydroxymethyl group is present which isα-oriented. As a consequence, the steroids of the invention have the14β-configuration, contrary to natural steroid hormones, such astestosterone and estradiol, which have a configuration 14α, 17β.

The steroids according to the invention satisfy the structural formulaI:

wherein

R₁ is O, (H,H), (H,OR), NOR, with R being hydrogen, (C₁₋₆) alkyl, (C₁₋₆)acyl;

R₂ is hydrogen, or (C₁₋₆) alkyl;

R₃ is hydrogen; or R₃ is (C₁₋₆) alkyl, (C₂₋₆) alkenyl, or (C₂₋₆)alkynyl, each optionally substituted by halogen;

R₄ is hydrogen, (C₁₋₆) alkyl, or (C₂₋₆) alkenyl;

R₅ is (C₁₋₆) alkyl;

R₆ is hydrogen, halogen, or (C₁₋₄) alkyl;

R₇ is hydrogen, or (C₁₋₆) alkyl;

R₈ is hydrogen, hydroxy, (C₁₋₆) alkoxy, halogen, or (C₁₋₆) alkyl;

R₉ and R₁₀ are independently hydrogen; or R₉ and R₁₀ are independently(C₁₋₆)alkyl, (C₂₋₆) alkenyl, (C₃₋₆) cycloalkyl, (C₅₋₆) cycloalkenyl, or(C₂₋₆) alkynyl, each optionally substituted by (C₁₋₄) alkoxy, orhalogen;

R₁₁ is hydrogen, SO₃H, (C₁₋₁₅) acyl; and the dotted lines indicateoptional bonds, selected from a Δ⁴, Δ⁵⁽¹⁰⁾, or Δ¹¹ double bond, or aΔ^(4.9) or Δ^(4.11) diene system.

The invention not only pertains to steroids which satisfy structuralformula I, but also to pharmaceutically acceptable salts or esters,prodrugs and precursors thereof.

The term (C₁₋₆) alkyl as used in the definition of formula I means abranched or unbranched alkyl group having 1-6 carbon atoms, like methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, andhexyl. Likewise, the term (C₁₋₄) alkyl means an alkyl group having 1-4carbon atoms. Preferred alkyl groups have 1-4 carbon atoms, and mostpreferred alkyl groups are methyl and ethyl.

The term (C₂₋₆) alkenyl means a branched or unbranched alkenyl grouphaving at least one double bond and 2-6-carbon atoms. Preferred alkenylgroups have 2-4 carbon atoms, such as vinyl and propenyl.

The term (C₂₋₆) alkynyl means a branched or unbranched alkynyl grouphaving at least one triple bond and 2-6 carbon atoms. Preferred alkynylgroups have 2-4 carbon atoms, such as ethynyl and propynyl.

The term (C₃₋₆) cycloalkyl means a cycloalkane ring having 3-6 carbonatoms, like cyclopropane, cyclobutane, cyclopentane and cyclohexane.

The term (C₅₋₆) cycloalkenyl means a cycloalkene ring having at leastone double bond and 5 or 6 carbon atoms.

The term (C₁₋₆) alkoxy means a branched or unbranched alkyloxy grouphaving 1-6 carbon atoms, like methyloxy, ethyloxy, propyloxy,isopropyloxy, butyloxy, isobutyloxy, tertiary butyloxy, pentyloxy, andhexyloxy. Likewise, the term (C₁₋₄) alkoxy means a branched orunbranched alkyloxy group having 1-4 carbon atoms. Preferred alkyloxygroups have 1-4 carbon atoms, and most preferred is methyloxy.

The term (C₁₋₆) acyl means an acyl group derived from a carboxylic acidhaving 1-6 carbon atoms, like formyl, acetyl, propanoyl, butyryl,2-methylpropanoyl, pentanoyl, pivaloyl, and hexanoyl. Likewise, the term(C₁₋₁₅) acyl means an acyl group derived from a carboxylic acid having1-15 carbon atoms. Also included within the definition of (C₁₋₆) acyl or(C₁₋₁₅) acyl are acyl groups derived from dicarboxylic acids, likehemi-maloyl, hemi-succinoyl, hemi-glutaroyl, and so on.

The term halogen means fluorine, chlorine, bromine, or iodine. Whenhalogen is a substituent at an alkyl group, like in the definition R₃,R₆, R₈, R₉ and R₁₀, Cl and F are preferred, F being most preferred.

The 14β,15β-methylene-17α-methanol steroid derivatives of this inventionhave the natural configurations 5α, 8β, 9α, 10β, and 13β. Theconfiguration at C-17 is 17α. The compounds of the invention may possessalso one or more additional chiral carbon atoms. They may therefore beobtained as a pure diastereomer, or as a mixture of diastereomers.Methods for obtaining the pure diastereomers are well known in the art,e.g. crystallization or chromatography.

For therapeutic use, salts of the compounds of formula I are thosewherein the counterion is pharmaceutically acceptable. However, salts ofthe acids according to formula I may also find use, for example, in thepreparation or purification of a pharmaceutically acceptable compound.All salts, whether pharmaceutically acceptable or not, are includedwithin the ambit of the present invention. Examples of salts of acidsaccording to the invention are mineral salts such as sodium salt,potassium salt, and salts derived from organic bases like ammonia,imidazole, ethylenediamine, triethylamine and the like.

The compounds of the invention as described hereinbefore in generalpossess an unexpected androgenic activity. Androgenic activity can bemeasured in various ways. Thus, the potency of androgens can bedetermined in vitro using the cytoplasmic androgen receptor from humanbreast tumor cells (MCF-7 cell line); see Bergink, E. W. et al,Comparison of the receptor binding properties of nandrolone andtestosterone under in vitro and in vivo conditions, J. Steroid Biochem.22, 831-836 (1985). It is also possible to use Chinese hamster ovary(CHO) cells transfected with the human androgen receptor (incubationtime 16 h, temperature 4° C.) and compared with the affinity of5α-dihydrotestosterone [according to the procedure described by Bergink,E. W. et al, J. Steroid Biochem. 19, 1563-1570 (1983)]. Thetransactivative androgen activity of the compounds of the invention canbe measured, e.g. in Chinese hamster ovary cells (CHO) transfected withthe human androgen receptor (hAR), in combination with a mouse mammarytumor virus (MMTV), and luciferase receptor gene (incubation time 16 h,temperature 37° C.) and compared with the activity of5α-dihydrotestosterone [according to the procedure described bySchoonen, W. G. E. J. et al, Analyt. Biochem. 261, 222-224 (1998)]. Forthe in vivo potency determination of androgens the classical Hershbergertest can be used. In this test the androgenic (increase in prostateweight) and anabolic activities [increase of the musculus levator ani(MLA)] of a compound are tested in immature castrated rats after dailyadministration for 7 days; see Hershberger, L. G. et al, Myotrophicactivity of 19-Nortestosterone and other steroids determined by modifiedlevator ani muscle method, Proceedings of the society for experimentalbiology and medicine 83, 175-180 (1953). Additionally, the effect of anandrogenic compound on LH suppression can be tested in mature castratedrats according to Kumar, N. et al, The biological activity of7alpha-methyl-19-nortestosterone is not amplified in male reproductivetract as is that of testosterone, Endocrinology 130, 3677-3683 (1992).

The preference goes to those compounds according to the invention whichexhibit a relatively high androgenic activity. Thus, the preferredcompounds of the invention are those satisfying the above structuralformula I, wherein R₁ is oxo, and the dotted lines indicate a Δ⁴ doublebond. More preferred are compounds wherein R₃ is 7α-methyl. Aspecifically preferred compound of the invention is(7α,14β,15β,17α)-17-(hydroxymethyl)-7-methyl-14,15-methyleneestr-4-en-3-one.

As androgenic hormones the steroids of the present invention can be usedin, inter alia, male contraception and male HRT (hormone replacementtherapy). Thus, e.g. male contraception may comprise a regimen ofadministration of hormones in which a progestagen serves to achieve acontraceptive effect and an androgen serves to supplement the resultingdecreased testosterone level. Another option is that male contraceptionis performed with an androgenic hormone alone. The androgens can also beused for androgen supplementation in the partially androgen deficientageing male. Next to the use in the male, the androgens of the inventionalso can be used in the female, e.g. as androgen replacement therapy inpostmenopausal women, or in androgen-deficient children.

The present invention also relates to a pharmaceutical compositioncomprising a steroid compound according to the invention mixed with apharmaceutically acceptable auxiliary, such as described in the standardreference, Gennaro et al, Remmington's Pharmaceutical Sciences, (18thed., Mack Publishing Company, 1990, see especially Part 8:Pharmaceutical Preparations and Their Manufacture). The mixture of thesteroid compounds according to the invention and the pharmaceuticallyacceptable auxiliary may be compressed into solid dosage units, such aspills, tablets, or be processed into capsules or suppositories. By meansof pharmaceutically suitable liquids the compounds can also be appliedas an injection preparation in the form of a solution, suspension,emulsion, or as a spray, e.g. nasal spray. For making dosage units, e.g.tablets, the use of conventional additives such as fillers, colorants,polymeric binders and the like is contemplated. In general anypharmaceutically acceptable additive which does not interfere with thefunction of the active compounds can be used. The steroid compounds ofthe invention may also be included in an implant, a vaginal ring, apatch, a gel, and any other preparation for sustained release.

Suitable carriers with which the compositions can be administeredinclude lactose, starch, cellulose derivatives and the like, or mixturesthereof used in suitable amounts.

Furthermore, the invention relates to the use of the steroid compoundaccording to the invention for the manufacture of a medicament in thetreatment of androgen-deficiency, such as in male or female HRT (hormonereplacement therapy). Accordingly, the invention also includes a methodof treatment in the field of male or female HRT, comprising theadministration to a male or female patient suffering from anandrogen-deficiency, of a compound as described hereinbefore (in asuitable pharmaceutical dosage form).

Further, the invention relates to the use of a steroid compoundaccording to the invention for the manufacture of a medicament havingcontraceptive activity (for which in the art the term “contraceptiveagent” is also used). Thus the invention also pertains to the medicalindication of contraception, i.e. a method of contraception comprisingthe administration to a subject, being a male, preferably a human male,of a compound as described hereinbefore (in a suitable pharmaceuticaldosage form), in combined therapy with a progestagen or not.

The androgens according to the invention can also be used in a kit formale contraception. Although this kit can comprise one or more androgensonly, it is preferred that it comprises means for the administration ofa progestagen and means for the administration of an androgen.

The latter means is a pharmaceutical formulation comprising compoundaccording to the invention as described hereinbefore, and apharmaceutically acceptable carrier.

The invention also pertains to a method of treatment comprisingadministering to a (notably human) male or female in need ofandrogen-supplementation a therapeutically effective amount of a14β,15β-methylene-17α-methanol steroid derivative as describedhereinbefore. This is irrespective of whether or not the need forandrogen-supplementation has arisen as a result of male contraceptioninvolving the administration of a sterilitant, such as a progestagen.

Further, the invention pertains to a method of contraception, comprisingadministering to a fertile male, notably human, a14β,15β-methylene-17α-methanol steroid derivative as describedhereinbefore in a dosage amount and regimen which is sufficient for saidcompound to be contraceptively effective per se. Alternatively, themethod of contraception provided by the present invention comprisesadministering to a fertile male, notably human, a contraceptivelyeffective combination of a sterilitant, such as a progestagen, and a14β,15β-methylene-17α-methanol steroid derivative as describedhereinbefore.

The compounds of the invention may be produced by various methods knownin the art of organic chemistry in general, and especially in the art ofthe chemistry of steroids (see, for example: Fried, J. et al, OrganicReactions in Steroid Chemistry, Volumes I and II, Van Nostrand ReinholdCompany, New York, 1972). Essential is the introduction of a14β,15β-methylene group and a (substituted) 17α-(hydroxymethyl) group tothe steroid nucleus.

A convenient starting material for the preparation of compounds offormula I wherein R₁ is oxo; R₂, R₇, R₈ and R₁₁ are hydrogen; R₃ and R₄are hydrogen or (C₁₋₆) alkyl; R₅ is methyl; R₆, R₉ and R₁₀ have thepreviously given meaning; and the dotted lines indicate a Δ⁴ doublebond, is for instance a compound of general formula II, wherein R₃ andR₄ are hydrogen or (C₁₋₆) alkyl, whose synthesis is known in literature,or which can be prepared using standard methods [see e.g. U.S. Pat. No.3,407,217 (1965; R₃═H, R₄═H), FR 1434172 (1966; R₃═CH₃, R₄═H), DE2539300 (1976; R₃═H, R₄═CH₃), WO 99/26962 (R₃═CH₃, R₄═CH₃)].

A possible synthesis route for compounds of the invention starts withthe transformation of compounds of formula II into Δ¹⁴-compounds offormula III using methods described in WO 00/53619. Addition of asuitable carbene intermediate to the Δ¹⁴ double bond results in a(14β,15β,17β)-3-methoxy-14,15-methyleneestra-1,3,5(10)-trien-17-olderivative [Helquist. P., in Comprehensive Organic Synthesis, Vol. 4, p.951, Pergamon Press, Oxford, N.Y. (1991); Nair, V., ibid., Vol. 4, p.999 (1991); Larock, R. C., Comprehensive Organic Transformations, VCHPublishers, Inc., 1989, p. 71]. Oxidation of the 17-hydroxy groupproduces a(14β,15β)-3-methoxy-14,15-methyleneestra-1,3,5(10)-trien-17-onederivative (for oxidations, see Hudlicky, M., Oxidations in OrganicChemistry, ACS Monograph 186, Washington, D.C., 1990) which serves asstarting material for the introduction of the 17-carbinol fragment.

The conversion of 17-oxo to 17-(CH₂OH) can be accomplished in severalways:

(a) 1: Wittig or Peterson reaction to a17-methyleneestra-1,3,5(10)-triene derivative [Maercker, A., in Org.Reactions 14, p. 270, Wiley, New York, 1965; Ager, D. J., in Org.Reactions 38, p. 1, Wiley, New York, 1990]; 2: hydroboration, forinstance by use of 9-BBN, disiamylborane, or thexylborane [see e.g.Zweifel, G. et al, in Org. Reactions 13, p. 1, Wiley, New York, 1963],resulting in the formation of a (17α)-estra-1,3,5(10)-triene-17-methanolderivative and/or the corresponding 17β isomer.

(b) 1: Conversion of the 17-ketone to a(17β)-spiroestra-1,3,5(10)-triene[17,2′]oxirane by reaction with e.g.trimethylsulfonium iodide/n-BuLi [Corey, E. J. et al, J. Am. Chem. Soc.87, 1353 (1965)]; 2: (Lewis)acid-catalyzed isomerization of the17β-oxirane to 17α-formyl [Rickborn, B., in Comprehensive OrganicSynthesis, Vol. 3, p. 733, Pergamon Press, Oxford, N.Y. (1991)]; 3:reduction of 17α-formyl to 17α-(CH₂OH).

(c) 1: Conversion of the 17-ketone to a 17-methylene compound; 2:epoxidation with e.g. a peroxy acid, such as m-chloroperbenzoic acid, toa (17β)-spiroestra-1,3,5(10)-triene[17,2′]oxirane; 3:(Lewis)acid-catalyzed isomerization to 17α-formyl as described under(b); 4: reduction of 17α-formyl to 17α-(CH₂OH).

(d) 1: Conversion of the 17-ketone to a 17β-oxirane as described under(b) and (c); 2: Lewis acid-catalyzed reduction to the 17-methanolsteroid [using e.g. NaBH₃CN/BF₃.Et₂O, see: Tone, H. et al, TetrahedronLett. 28, 4569 (1987)].

(e) 1: Reaction of the 17-ketone to the 17-cyano steroid by reactionwith tosylmethyl isocyanide [TosMIC, see Bull, J. R. et al, Tetrahedron31, 2151 (1975)]; 2: reduction of the cyano group to formyl bydiisobutylaluminum hydride; 3: reduction of the 17-formyl group to17-(CH₂OH).

(f) 1: Wittig condensation with (Ph)₃P═CHOMe; 2: hydrolysis of theresulting enol ether; 3: reduction of 17-formyl to 17-(CH₂OH).

(g) 1: Conversion of the 17-ketone to a 17β-oxirane as described under(b) and (c); 2: elimination to a estra-1,3,5(10),16-tetraene-17-methanolderivative; 3: hydrogenation of the Δ¹⁶ double bond.

(h) 1: Conversion of the 17-ketone to the corresponding enol triflate[see e.g. Cacchi, S. et al, Tetrahedron Lett. 25, 4821 (1984)]; 2:palladium-catalyzed alkoxycarbonylation of the latter to a alkylestra-1,3,5(10),16-tetraene-17-carboxylate [Cacchi, S. et al,Tetrahedron Lett. 26, 1109 (1985)]; 3: reduction of the latter to thecorresponding 17-methanol derivative; 4: hydrogenation of the Δ¹⁶ doublebond.

(i) 1: Conversion of the 17-ketone to a alkylestra-1,3,5(10),16-tetraene-17-carboxylate as described under (h); 2:1,4-reduction, e.g. by hydrogenation or by lithium or sodium in liquidammonia, to a alkyl estra-1,3,5(10)-triene-17-carboxylate derivative; 3:reduction of the ester to 17-(CH₂OH).

Some of these methods (e.g. b,c) result in the stereoselective formationof the 17α-(CH₂OH) isomer. Others (e.g. a) may give mixtures which canbe separated by chromatography or crystallization.

The(14β,15β,17α)-3-methoxy-14,15-methyleneestra-1,3,5(10)-triene-17-methanolderivatives thus obtained are subjected to Birch reduction andsubsequent hydrolysis to produce the(14β,15β,17α)-17-(hydroxymethyl)estr-4-ene-3-one derivatives of theinvention.

Optionally, a(14β,15β,17α)-3-methoxy-14,15-methyleneestra-1,3,5(10)-triene-17-carboxaldehydementioned above can be reacted with an (organometallic) compound offormula R₉M in which R₉ has the previously given meaning except forhydrogen, and M is Li, Na, K, MgX, ZnX, CeX₂, SiR₃ or SnR₃, to produce a17-(CHR₉OH) derivative which is usually a mixture of C-20 epimers. Thelatter can be separated whereafter Birch reduction and hydrolysis asdescribed above provides the(14β,15β,17α)-17-(CHR₉OH)-14,15-methyleneestr-4-en-3-one derivatives ofthe invention in which R₉ has the previously given meaning except forhydrogen.

Optionally, a(14β,15β,17α)-17-(CHR₉OH)-3-methoxy-14,15-methyleneestra-1,3,5(10)-trienecan be oxidized to obtain a 20-ketone which can then be reacted with an(organometallic) compound of formula R₁₀M, R₁₀ having the previouslygiven meaning except for hydrogen, and M having the previously givenmeaning. In that case Birch reduction and hydrolysis will provide17-(CR₉R₁₀OH) derivatives of the invention wherein R₉ and R₁₀ have thepreviously given meaning except for hydrogen.

Optionally, the 20-ketone can be reduced by reaction with LiAlH₄, NaBH₄or other reducing agents. In that case, 17-(CHR₉OH) derivatives areobtained of inverted stereochemistry at C-20. Epimerization at C-20 canalso be accomplished by means of a Mitsunobu reaction [Dodge, J. A. etal, Bioorg. & Med. Chem. Lett. 6, 1 (1996)], or by treatment withmethanesulfonyl chloride or p-toluenesulfonyl chloride followed byreaction with an oxygen nucleophile [e.g. potassium superoxide, seeCorey, E. J. et al, Tetrahedron Lett. 3183 (1975)]. Optionally, a(14β,15β,17α)-3-methoxy-14,15-methyleneestra-2,5(10)-diene-17-methanolderivative, i.e. the product obtained after the Birch reduction, can beoxidized to the corresponding 17-carboxaldehyde. Reaction with acompound of formula R₉M as described above and hydrolysis affords the17-(CHR₉OH) derivatives of the invention as already described above.This reaction sequence allows the introduction of substituents R₉, andanalogously, R₁₀, which would not survive a Birch reduction. Optionally,the 3-methoxy-2,5(10)-diene might also be converted to a more stablesystem, e.g. a 3,3-dimethoxyestr-5(10)-ene derivative or aestr-4-en-3-one cyclic 1,2-ethanediyl (dithio)acetal derivative, priorto oxidation and reaction with R₉M, and so on.

Compounds of formula I with substituents at C-3, C-4, C-7, C-11, C-13,C-1′, C-16 and C-17 other than those described under the definition offormula II, or compounds with R₁₁ other than hydrogen, or compoundswithout double bonds in the steroid nucleus, or with unsaturations otherthan a Δ⁴ double bond, can be prepared as follows.

Compounds of the invention in which R₁ is (H,H), (H,OR), NOR, and R isH, (C₁₋₆) alkyl, or (C₁₋₆) acyl can be prepared from compounds offormula I in which R₁ is oxo.

Compounds in which R₂ is (C₁₋₆)alkyl are obtained from compounds offormula I in which R₂ is hydrogen.

Compounds with substituents R₃ other than hydrogen can be prepared frome.g. (7α,17β)-7-ethenyl-17-hydroxyestr-4-en-3-one which can be preparedby copper(I)-catalyzed 1,6-addition of vinyllithium or a vinylmagnesiumcompound to e.g. (17β)-17-(acetyloxy)estra-4,6-diene-3-one [Syntex, DE1143199 (1963)]. Conversion to(7α)-7-ethenyl-3-methoxyestra-1,3,5(10)-trien-17-one and construction ofthe functionalized and/or unsaturated side-chain at C-7 from 7-ethenylare carried out using standard methods, and introduction of the14β,15β-methylene group and the side-chain at C-17 are accomplished asdescribed above. The precise sequence of reaction steps needed for theseoperations, and for the Birch reduction and the hydrolysis of theresulting estra-2,5(10)-diene, is dictated by methods common insynthetic strategy.

Compounds with substituents R₄ other than hydrogen or (C₁₋₆) alkyl canbe obtained from e.g.(11β)-11-(hydroxymethyl)-3-methoxyestra-1,3,5(10)-trien-17-one cyclic1,2-ethanediyl acetal [van den Broek, A. J. et al, Steroids 30, 481(1977)], or 3-methoxyestra-1,3,5(10)-triene-11,17-dione cyclic17-(1,2-ethanediyl acetal) [van den Broek, A. J. et al, Recl. Trav.Chim. Pays-Bas 94, 35 (1975)].

Compounds in which R₅ is e.g. ethyl can be prepared from e.g.13-ethylgon-4-ene-3,17-dione [Brito, M. et al, Synth. Comm. 26, 623(1996)].

16-Substituted compounds can be obtained via alkylation at C-16 of a(14β,15β)-3-methoxy-14,15-methyleneestra-1,3,5(10)-trien-17-onederivative.

17β-Alkylated compounds of formula I can e.g. be obtained via alkylationof a alkyl(14β,15β,17α)-3-methoxy-14,15-methyleneestra-1,3,5(10)-triene-17-carboxylate.Compounds of formula I in which R₈ is hydroxy, (C₁₋₆) alkoxy, or halogencan be prepared from a (17β)-spiroestra-1,3,5(10)-triene[17,2′]oxirane.

Compounds of the invention in which R₁₁ is SO₃H or (C₁₋₁₅) acyl areobtained from compounds of formula I in which R₁₁ is hydrogen.

Compounds of the invention without unsaturations in the steroid nucleusare produced from Δ⁴ compounds wherein R₁ is oxo.

Compounds of the invention having Δ⁵⁽¹⁰⁾ double bond, or a Δ^(4.9) dienesystem are produced from the Δ^(2.5(10)) dienes obtained after the Birchreduction.

Compounds having a Δ¹¹ double bond can be prepared from e.g.estra-4,11-diene-3,17-dione [Broess, A. I. A. et al, Steroids 57, 514(1992)].

The invention will be further explained hereinafter with reference tothe following Examples.

EXAMPLE 1

(7α,14β,15β,17α)-17-(Hydroxymethyl)-7-methyl-14,15-methyleneestr-4-en-3-one

i)—A solution of(7α,17β)-3-methoxy-7-methylestra-1,3,5(10),14-tetraen-17-ol [Segaloff,A. et al, Steroids 22, 99 (1973); 25.4 g] and diiodomethane (27 ml) indry dichloromethane (500 ml) was cooled to 0° C. A solution ofdiethylzinc in hexane (15% wt., 300 ml) was added in 1 h and thereaction mixture was stirred for 21 h at room temperature. Ice was addedand the mixture was poured into a saturated aqueous solution of ammoniumchloride. The product was extracted into diethyl ether; the combinedorganic phases were washed with brine, dried over sodium sulfate, andconcentrated under reduced pressure. Column chromatography afforded(7α,14β,15β,17β)-3-methoxy-7-methyl-14,15-methyleneestra-1,3,5(10)-trien-17-ol(6.50 g).

ii)—A solution of the product obtained in the previous step (6.50 g) inacetone (325 ml), cooled to 5° C., was treated with Jones reagent (8 M,11.9 ml). After 15 min. stirring at 5-10° C., 2-propanol was added andthe mixture was filtered. The filtrate was concentrated; water was addedand the product was extracted into ethyl acetate. The combined organicphases were washed with brine, dried over sodium sulfate andconcentrated under reduced pressure, to give(7α,14β,15β)-3-methoxy-7-methyl-14,15-methyleneestra-1,3,5(10)-trien-17-one(6.57 g). The product was used in the following step without furtherpurification.

iii)—Potassium tert-butoxide (6.1 g) was added in portions to a solutionof the product obtained in the previous step (3.81 g) in a mixture ofdry tetrahydrofuran (26 ml) and dry dimethyl sulfoxide (65 ml),containing trimethylsulfonium iodide (8.4 g). The reaction mixture wasstirred at room temperature for 3 h and then poured into an aqueoussolution of ammonium chloride. The product was extracted into ethylacetate; the combined organic phases were washed with brine, dried oversodium sulfate, and concentrated under reduced pressure, to obtain(7α,14β,15β,17β)-3-methoxy-7-methyl-14,15-methylenespiroestra-1,3,5(10)-triene[17,2′]oxirane(3.76 g). The product was used in the following step without furtherpurification.

iv)—A solution of the product obtained in the previous step (3.76 g) in1,4-dioxane (113 ml) was treated with an aqueous solution of perchloricacid (70%, 1.80 ml). The reaction mixture was stirred at roomtemperature for 2 h and then treated with another portion of perchloricacid (0.36 ml). The mixture was stirred for another 2 h and then pouredinto a saturated aqueous solution of sodium hydrogencarbonate. Theproduct was extracted into ethyl acetate; the combined organic phaseswere washed with brine, dried over sodium sulfate and concentrated underreduced pressure, to give(7α,14β,15β,17α)-3-methoxy-7-methyl-14,15-methyleneestra-1,3,5(10)-triene-17-carboxaldehyde(4.11 g). The product was used in the following step without furtherpurification.

v)—A solution of the product obtained in the previous step (3.7 g) indry tetrahydrofuran (24 ml) was added dropwise to an ice-cooledsuspension of lithium aluminium hydride (1.90 g) in tetrahydrofuran (24ml). After 1 h stirring, the reaction was quenched by addition of asaturated aqueous solution of sodium sulfate. Ethyl acetate was added,and the mixture was filtered over dicalite. The organic phase wasseparated from the aqueous phase and washed with brine, dried oversodium sulfate and concentrated under reduced pressure. Columnchromatography afforded(7α,14β,15β,17α)-3-methoxy-7-methyl-14,15-methyleneestra-1,3,5(10)-triene-17-methanol(1.30 g).

vi)—The product obtained in the previous step (1.30 g) in drytetrahydrofuran (27 ml) was added to a refluxing solution of lithium(0.82 g) in liquid ammonia (54 ml). The reaction mixture was stirred atreflux temperature for 45 min. tert-Butanol (2.7 ml) was added and themixture was stirred for 30 min. Ethanol was added and the ammonia wasallowed to evaporate. Water was added and the product was extracted intoethyl acetate. The combined organic phases were washed with a saturatedaqueous solution of ammonium chloride and brine, dried over sodiumsulfate and concentrated under reduced pressure, to give(7α,14β,15β,17α)-3-methoxy-7-methyl-14,15-methyleneestra-2,5(10)-diene-17-methanol(1.17 g). The product was used in the following step without furtherpurification.

vii)—A solution of the product obtained in the previous step (1.17 g) inacetone (23 ml) was treated with hydrochloric acid (6 M, 2 ml). After1.5 h stirring at room temperature, a saturated aqueous solution ofsodium hydrogencarbonate was added and the product was extracted intoethyl acetate. The combined organic phases were washed with a brine,dried over sodium sulfate and concentrated under reduced pressure.Column chromatography afforded(7α,14β,15β,17α)-17-(hydroxymethyl)-7-methyl-14,15-methyleneestr-4-en-3-one(0.40 g). M.p. 137-140° C., [α]_(D) ²⁰=+73.0° (c=1.00, dioxane), ¹H NMR(CDCl₃) δ5.80 (bs, 1H), 3.69 (m, 1H), 3.50 (m, 1H), 1.09 (s, 3H), 0.62(d, 3H, J=7.1 Hz), 0.47 (dd, 1H, J=8.3 and 5.1 Hz), 0.28 (dd, 1H, J=5.1and 3.5 Hz).

EXAMPLE 2

(7α,14,β15β,17α)-17-(Hydroxymethyl)-7-methyl-14,15-methyleneestr-5(10)-en-3-one

A solution of(7α,14β,15β,17α)-3-methoxy-7-methyl-14,15-methyleneestra-2,5(10)-diene-17-methanol(Example 1, step vi; 7.38 g) in a mixture of methanol (68 ml) andtetrahydrofuran (48 ml) was treated with a solution of oxalic acid (2.38g) in water (40 ml). After 1 h stirring at room temperature, thereaction mixture was poured into a saturated aqueous solution of sodiumhydrogencarbonate and the product was extracted into ethyl acetate. Thecombined organic phases were washed with brine, dried over sodiumsulfate and concentrated under reduced pressure. Column chromatographyafforded(7α,14β,15β,17α)-17-(hydroxyethyl)-7-methyl-14,15-methyleneestr-5(10)-en-3-one(4.27 g). ¹H NMR (CDCl₃) δ3.69 (m, 1H), 3.51 (t, 1H, J=9.0 Hz), 2.72(bs, 2H), 2.46 (bs, 2H), 1.04 (s, 3H), 0.69 (d, 3H, J=7.1 Hz), 0.48(dd,1H, J=8.3 and 5.1 Hz), 0.27 (dd, 1H, J=5.1 and 3.1 Hz).

EXAMPLE 3

(7α,14β,15β17α)-17-(Hydroxymethyl)-7-methyl-14,15-methyleneestra-4,9-dienes-3-one

Phenyltrimethylammonium tribromide (1.01 g) was added to a solution of(7α,14β,15β,17α)-17-(hydroxymethyl)-7-methyl-14,15-methyleneestr-5(10)-en-3-one(Example 2, 0.85 g) in dry pyridine (25 ml). After 1.5 h stirring atroom temperature the mixture was poured into ice-water and the productwas extracted into ethyl acetate. The combined organic phases werewashed with a saturated aqueous solution of sodium thiosulfate andbrine, dried over sodium sulfate and concentrated under reducedpressure. Column chromatography provided(7α,14β,15β,17α)-17-(hydroxymethyl)-7-methyl-14,15-methyleneestra-4,9-dien-3-one(0.18 g). ¹H NMR (CDCl₃) δ5.68 (s, 1H), 3.72 (m, 1H), 3.60 (m, 1H), 3.01(bs, 1H), 1.11 (s, 3H), 0.69 (d, 3H, J=7.1 Hz), 0.52 (dd, 1H, J=8.3 and5.5 Hz), 0.38 (dd, 1H, J=5.5 and 3.9 Hz).

EXAMPLE4

(7α,14β,15β,17α)-17-(Hydroxymethyl)-4,7-dimethyl-14,15-methyleneestr-4-en-3-one

i)—A solution of(7α,14β,15β,17α)-17-(hydroxymethyl)-7-methyl-14,15-methyleneestr-4-en-3-one(Example 1, 0.40 g) in a mixture of formaldehyde (37 wt. % solution inwater, 0.24 ml), triethylamine (0.288 ml), thiophenol (0.276 ml) andethanol (0.721 ml) was stirred at room temperature overnight. Thereaction mixture was poured into a aqueous solution of potassiumhydroxide (0.5 M) and the product was extracted into ethyl acetate. Thecombined organic phases were washed with a aqueous solution of potassiumhydroxide (0.5 M) and brine, dried over sodium sulfate and concentratedunder reduced pressure. Column chromatography afforded(7α,14β,15β,17α)-17-(hydroxymethyl)-7-methyl-4-[(phenylthio)methyl]-14,15-methyleneestr-4-en-3-one(0.13 g).

ii)—A solution of the product obtained in the previous step (0.13 g) inacetone (4.8 ml) was treated with Raney-nickel (suspension in ethanol,0.5 ml) and the mixture was heated at reflux temperature for 45 min. Themixture was filtered and the filtrate was concentrated under reducedpressure. Column chromatography afforded(7α,14β,15β,17α)-17-(hydroxymethyl)-4,7-dimethyl-14,15-methyleneestr-4-en-3-one(0.050 g). ¹H NMR (CDCl₃) δ3.69 (dt, part A of AB system, 1H, J=10.6 and5.1 Hz), 3.50 (ddd, part B of AB system, 1H, J=10.6, 8.3 and 4.7 Hz),2.76 (dd, 1H, J=13.4 and 3.1 Hz), 1.78 (t, 3H, J=1.2 Hz), 1.08 (s, 3H),0.61 (d, 3H, J=7.1 Hz), 0.47 (dd, 1H, J=8.3 and 5.1 Hz), 0.27 (dd, 1H,J=5.1 and 3.5 Hz).

EXAMPLE 5

(7α,14β,15β,17α)-7-Ethyl-17-(hydroxymethyl)-14,15-methyleneestr-4-en-3-one

i)—Chlorotrimethylsilane (19 ml) was added in 5 min. to a suspension of(17α)-17-hydroxy-19-norpregna-4,6-dien-20-yn-3-one [Syntex S. A., GB935116 (1958); 18.0 g] in a mixture of dichloromethane (300 ml) andpyridine (25 ml), cooled to 0° C. After 2 h stirring at 0° C. thereaction mixture was poured into a saturated aqueous solution of sodiumhydrogencarbonate. The product was extracted into dichloromethane; thecombined organic phases were washed with water and brine, dried oversodium sulfate and concentrated under reduced pressure, to afford(17α)-17-[(trimethylsilyl)oxy]-19-norpregna-4,6-dien-20-yn-3-one (22.3g). The product was used in the following step without furtherpurification.

ii)—A mixture of lithium (5.0 g) and dry diethyl ether (200 ml) wascooled to −30° C. Bromoethane (26.9 ml) was added dropwise whereafterthe resulting solution of ethyllithium was transferred to a suspensionof copper(I) iodide (30.6 g) in dry tetrahydrofuran (140 ml), cooled to−30° C. The resulting cuprate solution was stirred for 45 min. at thattemperature and a solution of the product obtained in the previous step(20.0 g) in dry tetrahydrofuran (160 ml) was added dropwise. After 45min. stirring at −25° C., chlorotrimethylsilane (20 ml) was added andstirring was continued for another 30 min. The reaction mixture waspoured into a saturated aqueous solution of ammonium chloride and theproduct was extracted into ethyl acetate. The combined organic phaseswere washed with a saturated aqueous solution of ammonium chloride andbrine, dried over sodium sulfate and concentrated under reducedpressure, to give(7α,17α)-7-ethyl-3,17-bis[(trimethylsilyl)oxy]-19-norpregna-3,5-dien-20-one(29.5 g). The product was used in the following step without furtherpurification.

iii)—A solution of the product obtained in the previous step (29.5 g) inacetone (400 ml) was treated with hydrochloric acid (2.3 M, 20 ml).After 1.5 h stirring at room temperature, the reaction mixture wasneutralized with a saturated aqueous solution of sodiumhydrogencarbonate. The acetone was removed under reduced pressure andthe product was extracted into ethyl acetate. The combined organicphases were washed with brine, dried over sodium sulfate andconcentrated under reduced pressure, to give(7α,17α)-7-ethyl-17-hydroxy-19-norpregn-4-en-20-yn-3-one (19.5 g). Theproduct was used in the following step without further purification.

iv)—Hydrochloric acid (6 M, 240 ml) was added dropwise to a suspensionof dicalite (240 g) in methanol (1200 ml). After 20 min. stirring atroom temperature the dicalite was collected by fitration and washed withwater until neutral. Then, it was suspended in water (960 ml). Withvigorous stirring, copper(II) nitrate trihydrate (145 g) was added,followed by careful addition of a solution of sodium carbonate (72.2 g)in water (360 ml). After 30 min. stirring, the product was collected byfiltration and washed with water until neutral. The product was dried at80° C. under reduced pressure, to give copper(II) carbonate on dicalite(310 g). A mixture of the product obtained under iii (19.5 g) andcopper(II) carbonate on dicalite (70 g) in toluene (330 ml) was heatedat reflux temperature for 9 h under removal of water by use of aDean-Stark trap. The reaction mixture was filtered, the residuethoroughly washed with ethyl acetate, and the filtrate was concentratedunder reduced pressure. Column chromatography gave(7α)-7-ethylestr-4-ene-3,17-dione (9.14 g).

v)—A solution of the product obtained in the previous step (9.14 g),copper(II) bromide (13.6 g), and lithium bromide (2.64 g) inacetonitrile (285 ml) was stirred at room temperature for 4 h. Thereaction mixture was poured into water and the product extracted intoethyl acetate. The combined organic phases were was washed with asaturated aqueous solution of ammonium chloride and brine, dried oversodium sulfate and concentrated under reduced pressure. Columnchromatography afforded(7α)-7-ethyl-3-hydroxyestra-1,3,5(10)-trien-17-one (6.54 g).

vi)—A mixture of the product obtained in the previous step (6.54 g), drypotassium carbonate (18.6 g), iodomethane (5.6 ml), and drydimethylformamide (22 ml) was stirred at room temperature for 3.5 h. Thereaction mixture was poured into water and the product extracted intoethyl acetate. The combined organic phases were washed with water, asaturated aqueous solution of ammonium chloride and brine, dried oversodium sulfate and concentrated under reduced pressure, to give(7α)-7-ethyl-3-methoxyestra-1,3,5(10)-trien-17-one (6.77 g). The productwas used in the following step without further purification.

vii)—A solution of diisopropylamine (6.15 ml) in dry tetrahydrofuran (70ml) was cooled to −30° C. n-BuLi (1.6 M solution in hexanes, 27.5 ml)was added dropwise and stirring was continued for 30 min. The reactionmixture was cooled to −50° C. and a solution of the product obtained inthe previous step (6.95 g) in dry tetrahydrofuran (100 ml) was addeddropwise. Stirring was continued for 1 h. After cooling to −60° C.,chlorotrimethylsilane (11.1 ml) was added. The mixture was stirred for20 min. and then treated with a solution of phenyltrimethylammoniumtribromide (10.0 g) in dry pyridine (31 ml). After 1 h stirring at −60°C., the mixture was poured into water and the product was extracted intoethyl acetate. The combined organic phases were washed with a saturatedaqueous solution of sodium hydrogencarbonate and brine, dried oversodium sulfate and concentrated under reduced pressure. Columnchromatography afforded(7α,16α)-16-bromo-7-ethyl-3-methoxyestra-1,3,5(10)-trien-17-one (8.75g).

viii)—A mixture of the product obtained in the previous step (8.75 g),lithium bromide (12.7 g) and lithium carbonate (10.9 g) in drydimethylformamide (77 ml) was heated under reflux for 3.25 h. Aftercooling, the reaction mixture was poured into water and the product wasextracted into ethyl acetate. The combined organic phases were washedwith water and brine, dried over sodium sulfate and concentrated underreduced pressure. Column chromatography afforded(7α)-7-ethyl-3-methoxyestra-1,3,5(10),14-tetraen-17-one (4.31 g) and(7α,14β)-7-ethyl-3-methoxyestra-1,3,5(10),15-tetraen-17-one (1.0 g).

ix)—A solution of sodium borohydride (0.21 g) and sodium hydroxide (0.44g) in methanol (50 ml) was added dropwise to a solution of(7α)-7-ethyl-3-methoxyestra-1,3,5(10),14-tetraen-17-one (4.31 g) indichloromethane (12 ml) and methanol (20 ml), cooled to 0° C. Thereaction mixture was stirred for 1.5 h, quenched with acetone (4 ml),and then poured into a saturated aqueous solution of ammonium chloride.The product was extracted into ethyl acetate; the combined organicphases were washed with brine, dried over sodium sulfate andconcentrated under reduced pressure, to give(7α,17β)-7-ethyl-3-methoxyestra-1,3,5(10),14-tetraen-17-ol (4.28 g). Theproduct was used in the following step without further purification.

x)—Following a procedure analogous to that described under i of Example1, the product obtained in the previous step (24.27 g) was converted to(7α,14β,15β,17β)-7-ethyl-3-methoxy-14,15-methyleneestra-1,3,5(10)-trien-17-ol(12.82 g).

xi)—Following a procedure analogous to that described under ii ofExample 1, the product obtained in the previous step (14.03 g) wasconverted to(7α,14β,15β)-7-ethyl-3-methoxy-14,15-methyleneestra-1,3,5(10)-trien-17-one(7.34 g).

xii)—Following a procedure analogous to that described under iii ofExample 1, the product obtained in the previous step (6.80 g) wasconverted to(7α,14β,15β,17β)-7-ethyl-3-methoxy-14,15-methylenespiroestra-1,3,5(10)-triene[17,2′]oxirane(7.24 g).

xiii)—Following a procedure analogous to that described under iv ofExample 1, the product obtained in the previous step (7.24 g) wasconverted to(7α,14β,15β,17α)-7-ethyl-3-methoxy-14,15-methyleneestra-1,3,5(10)-triene-17-carboxaldehyde(8.48 g).

xiv)—Following a procedure analogous to that described under v ofExample 1, the product obtained in the previous step (8.48 g) wasconverted to(7α,14β,15β,17α)-7-ethyl-3-methoxy-14,15-methyleneestra-1,3,5(10)-triene-17-methanol(1.23 g).

xv)—Following a procedure analogous to that described under vi ofExample 1, the product obtained in the previous step (1.23 g) wasconverted to(7α,14β,15β,17α)-7-ethyl-3-methoxy-14,15-methyleneestra-2,5(10)-diene-17-methanol(1.19 g).

xvi)—Following a procedure analogous to that described under vii ofExample 1, the product obtained in the previous step (1.19 g) wasconverted to(7α,14β,15β,17α)-7-ethyl-17-(hydroxymethyl)-14,15-methyleneestr-4-en-3-one(0.40 g). ¹H NMR (CDCl₃) δ5.82 (m, 1H), 3.69 (dt, part A of AB system,1H, J=10.6 and 5.5 Hz), 3.51 (ddd, part B of AB system, 1H, J=10.6, 7.9and 4.7 Hz), 1.09 (s, 3H), 0.79 (t, 3H, J=7.5 Hz), 0.45 (dd, 1H, J=8.3and 5.5 Hz), 0.27 (dd, 1H, J=5.5 and 3.5 Hz).

EXAMPLE 6

(7α,14β,15β,17α)-13-Ethyl-17-(hydroxymethyl)-7-methyl-14,15-methylenegon-4-en-3-one

i)—Tetrapropylammonium perruthenate (1.3 g) was added to a solutionof(7α,17β)-13-ethyl-3-methoxy-7-methylgona-1,3,5(10)-trien-17-ol [FRAD87961 (1966); 19.5 g] and 4-methylmorpholine N-oxide (21.5 g) in acetone(513 ml). After 30 min. stirring at room temperature the reactionmixture was filtered over dicalite and silica. The filtrate wasconcentrated under reduced pressure. Column chromatography of the crudeproduct gave (7α)-13-ethyl-3-methoxy-7-methylgona-1,3,5(10)-trien-17-one(11.0 g).

ii)—p-Toluenesulfonic acid (0.41 g) was added to a solution of theproduct obtained in the previous step (9.9 g) in a mixture of ethyleneglycol (13.3 ml) and triethyl orthoformate (23.9 ml). The reactionmixture was stirred at room temperature for 3 h. Additionalp-toluenesulfonic acid (0.41 g) was added and stirring was continued for2 h. Water was added and stirring was continued for another 1 h. Theproduct was extracted into ethyl acetate; the combined organic phaseswere washed with a saturated aqueous solution of sodiumhydrogencarbonate and brine, dried over sodium sulfate and concentratedunder reduced pressure, to give(7α)-13-ethyl-3-methoxy-7-methylgona-1,3,5(10)-trien-17-one cyclic1,2-ethanediyl acetal and starting material (10.5 g, ratio 1:1). Theprocedure was repeated in order to achieve complete conversion ofstarting material. The product (9.8 g) was used in the following stepwithout further purification.

iii)—Phenyltrimethylammonium tribromide (8.25 g) was added to a solutionof the product obtained in the previous step (9.80 g) in drytetrahydrofuran (55 ml). After 1 h stirring additionalphenyltrimethylammonium tribromide (4.12 g) was added and stirring wascontinued for an additional 1 h. The reaction mixture was poured into asaturated aqueous solution of sodium thiosulfate. The product wasextracted into ethyl acetate; the combined organic phases were washedwith water and brine, dried over sodium sulfate and concentrated underreduced pressure, to give(7α,16α)-16-bromo-13-ethyl-3-methoxy-7-methylgona-1,3,5(10)-trien-17-onecyclic 1,2-ethanediyl acetal (14.5 g). The product was used in thefollowing step without further purification.

iv)—A solution of the product obtained in the previous step (14.5 g) indry dimethyl sulfoxide (55 ml) was treated with potassium tert-butoxide(12.4 g) and the reaction mixture was stirred at room temperature for1.5 h. Additional potassium tert-butoxide (12.4 g) was added and thereaction mixture was stirred for another 3 h at 40° C. The mixture waspoured into a saturated aqueous solution of ammonium chloride and theproduct was extracted into ethyl acetate. The combined organic phaseswere washed with water and brine, dried over sodium sulfate andconcentrated under reduced pressure. Column chromatography afforded(7α)-13-ethyl-3-methoxy-7-methylgona-1,3,5(10),15-tetraen-17-one cyclic1,2-ethanediyl acetal (6.30 g).

v)—A solution of the product obtained in the previous step (6.3 g) indry toluene (162 ml) was treated with pyridinium p-toluenesulfonate(4.21 g) and heated under reflux for 1 h. After cooling, the reactionmixture was poured into a saturated aqueous solution of sodiumhydrogencarbonate and the product was extracted into ethyl acetate. Thecombined organic phases were washed with brine, dried over sodiumsulfate and concentrated under reduced pressure, to give(7α)-13-ethyl-3-methoxy-7-methylgona-1,3,5(10),14-tetraen-17-one cyclic1,2-ethanediyl acetal (6.5 g). The product was used in the followingstep without further purification.

vi)—A solution of the product obtained in the previous step (6.5 g) indry toluene (251 ml) was treated with p-toluenesulfonic acid (3.5 g) andheated under reflux for 45 min. After cooling, the reaction mixture waspoured into a saturated aqueous solution of sodium hydrogencarbonate andthe product was extracted into ethyl acetate. The combined organicphases were washed with water and brine, dried over sodium sulfate andconcentrated under reduced pressure, to give(7α)-13-ethyl-3-methoxy-7-methylgona-1,3,5(10),14-tetraen-17-one (5.9g). The product was used in the following step without furtherpurification.

vii)—Following a procedure analogous to that described under v ofExample 1, the product obtained in the previous step (5.9 g) wasconverted to(7α,17β)-13-ethyl-3-methoxy-7-methylgona-1,3,5(10),14-tetraen-17-ol (4.4g).

viii)—Following a procedure analogous to that described under i ofExample 1, the product obtained in the previous step (2.9 g) wasconverted to(7α,14β,15β,17β)-13-ethyl-3-methoxy-7-methyl-14,15-methylenegona-1,3,5(10)-trien-17-ol(1.4 g).

ix)—Following a procedure analogous to that described under ii ofExample 1, the product obtained in the previous step (1.4 g) wasconverted to(7α,14β,15β)-13-ethyl-3-methoxy-7-methyl-14,15-methylenegona-1,3,5(10)-trien-17-one(1.4 g).

x)—Following a procedure analogous to that described under iii ofExample 1, the product obtained in the previous step (1.3 g) wasconverted to(7α,14β,15β,17β)-13-ethyl-3-methoxy-7-methyl-14,15-methylenespirogona-1,3,5(10)-triene[17,2′]oxirane(1.36 g).

xi)—Following a procedure analogous to that described under iv ofExample 1, the product obtained in the previous step (1.36 g) wasconverted to(7α,14β,15β,17α)-13-ethyl-3-methoxy-7-methyl-14,15-methylenegona-1,3,5(10)-triene-17-carboxaldehyde(1.35 g).

xii)—Following a procedure analogous to that described under v ofExample 1, the product obtained in the previous step (1.35 g) wasconverted to(7α,14β,15β,17α)-13-ethyl-3-methoxy-7-methyl-14,15-methylenegona-1,3,5(10)-triene-17-methanol(0.80 g).

xiii)—Following a procedure analogous to that described under vi ofExample 1, the product obtained in the previous step (0.60 g) wasconverted to(7α,14β,15β,17α)-13-ethyl-3-methoxy-7-methyl-14,15-methylenegona-2,5(10)-diene-17-methanol(0.60 g).

xiv)—Following a procedure analogous to that described under vii ofExample 1, the product obtained in the previous step (0.60 g) wasconverted to(7α,14β,15β,17α)-13-ethyl-17-(hydroxymethyl)-7-methyl-14,15-methylenegon-4-en-3-one(0.17 g). ¹H NMR (CDCl₃) δ5.79 (bs, 1H), 3.73 (m, 1H), 3.47 (m, 1H),0.92 (t, 3H, J=7.5 Hz), 0.59 (d, 3H, J=7.1 Hz). (dd, 1H, J=7.9 and 5.1Hz), 0.41 (dd, 1H, J=5.1 and 3.5 Hz).

EXAMPLE 7

(7α,14β,15β16β,17α)-17-(Hydroxymethyl)-7,16-dimethyl-14,15-methyleneestra-4-en-3-one

i)—A solution of lithium bis(trimethylsilyl)amide (20.2 mmol) intetrahydrofuran (35 ml) was cooled to −40° C. A solution of(7α,14β,15β)-3-methoxy-7-methyl-14,15-methyleneestra-1,3,5(10)-trien-17-one (Example 1, step ii; 5.60 g) in dry tetrahydrofuran(24 ml) was added dropwise and the reaction mixture was stirred for 30min. Then, at −30° C., iodomethane (2.4 ml) was added and stirring wascontinued for 45 min. The mixture was poured into a saturated aqueoussolution of ammonium chloride and the product was extracted into ethylacetate. The combined organic phases were washed with brine, dried oversodium sulfate and concentrated under reduced pressure, to give(7α,14β,15β,16α)-3-methoxy-7,16-dimethyl-14,15-methyleneestra-1,3,5(10)-trien-17-one(5.99 g). The product was used in the following step without furtherpurification.

ii)—A mixture of methyltriphenylphosphonium bromide (17 g), potassiumtert-butoxide (4.4 g) and dry toluene (173 ml) was heated under refluxfor 1 h. A solution of the ketone obtained in the previous step (5.04 g)in dry toluene (40 ml) was added dropwise and heating was continued for3 h. After cooling, the reaction mixture was poured into a saturatedaqueous solution of ammonium chloride. The product was extracted intoethyl acetate; the combined organic phases were washed with brine, driedover sodium sulfate and concentrated under reduced pressure. Columnchromatography afforded(7α,14β,15β,16β)-3-methoxy-7,16-dimethyl-17-methylene-14,15-methyleneestra-1,3,5(10)-triene(3.61 g).

iii)—m-Chloroperbenzoic acid (70-75%, 2.3 g) was added to a solution ofthe product obtained in the previous step (3.0 g) in dry dichloromethane(51 ml), containing solid sodium hydrogencarbonate (3 g). The reactionmixture was stirred at room temperature for 3 h; additional portions ofm-chloroperbenzoic acid (70-75%, 0.77 g) were added after 1 h and 2 h,respectively. The reaction was poured into a saturated aqueous solutionof sodium sulfite and the product was extracted into dichloromethane.The combined organic phases were washed with a aqueous solution ofsodium hydroxide (10%) and brine, dried over sodium sulfate andconcentrated under reduced pressure, to give(7α,14β,15β,16β,17β)-3-methoxy-7,16-dimethyl-14,15-methylenespiroestra-1,3,5(10)-triene[17,2′]oxirane(2.85 g). The product was used in the next step without furtherpurification.

iv)—Following a procedure analogous to that described under iv ofExample 1, the product obtained in the previous step (2.85 g) wasconverted to(7α,14β,15β,16β,17α)-3-methoxy-7,16-dimethyl-14,15-methyleneestra-1,3,5(10)-triene-17-carboxaldehyde(2.99 g).

v)—Following a procedure analogous to that described under v of Example1, the product obtained in the previous step (2.99 g) was converted to(7α,14β,15β,16β,17α)-3-methoxy-7,16-dimethyl-14,15-methyleneestra-1,3,5(10)-triene-17-methanol(0.30 g).

vi)—Following a procedure analogous to that described under vii ofExample 1, the product obtained in the previous step (0.30 g) wasconverted to(7α,14β,15β,16β,17α)-3-methoxy-7,16-dimethyl-14,15-methyleneestra-2,5(10)-diene-17-methanol(0.31 g).

vii)—Following a procedure analogous to that described under vii ofExample 1, the product obtained in the previous step (0.31 g) wasconverted to(7α,14β,15β,16β,17α-17-(hydroxymethyl)-7,16-dimethyl-14,15-methyleneestr-4-en-3-one(0.053 g). ¹H NMR (CDCl₃) δ5.80 (m, 1H), 3.64 (m, 2H), 1.09 (s, 3H),1.01 (d, 3H, J=6.7 Hz), 0.62 (d, 3H, J=7.1 Hz). 0.38 (dd, 1H, J=7.9 and5.1 Hz), 0.25 (dd, 1H, J=5.1 and 3.5 Hz).

EXAMPLE 8

(7α,14β,15β,17β)-17-Hydroxy-17-(hydroxymethyl)-7-methyl-14,15-methyleneestr-4-en-3-one

i)—Potassium hydroxide (3.28 g) was added to a solution of(7α,14β,15β,17β)-3-methoxy-7-methyl-14,15-methylenespiroestra-1,3,5(10)-triene[17,2′]oxirane(Example 1, step iii; 5.00 g) in a mixture of dimethyl sulfoxide (147ml) and water (25.3 ml). The reaction mixture was stirred at 100° C.overnight and then poured into a aqueous solution of ammonium chloride.The product was extracted into ethyl acetate; the combined organicphases were washed with brine, dried over sodium sulfate, andconcentrated under reduced pressure. Column chromatography gave(7α,14β15β,17β)-17-(hydroxymethyl)-3-methoxy-7-methyl-14,15-methylenesestra-1,3,5(10)-trien-17-ol(1.02 g).

ii)—Following a procedure analogous to that described under vi ofExample 1, the product obtained in the previous step (1.02 g) wasconverted to(7α,14β,15β,17β)-17-(hydroxymethyl)-3-methoxy-7-methyl-14,15-methyleneestra-2,5(10)-dien-17-ol(1.05 g).

iii)—Following a procedure analogous to that described under vii ofExample 1, the product obtained in the previous step (1.05 g) wasconverted to(7α,14β,15β17β)-17-hydroxy-17-(hydroxymethyl)-7-methyl-14,15-methyleneestr-4-en-3-one(0.12 g). ¹H NMR (CDCl₃) δ5.80 (bs, 1H), 3.63 (dd, part A of AB system,1H, J=10.6 and 4.7 Hz), 3.46 (dd, part B of AB system, 1H, J=10.6 and5.1 Hz), 1.11 (s, 3H), 1.10 (dd, 1H, J=4.7 and 3.9 Hz), 0.61 (d, 3H,J=7.1 Hz), 0.54 (dd, 1H, J=8.3 and 4.7 Hz).

EXAMPLE 9

(7α,14β,15β,17β)-17-[(Acetyloxy)methyl]-17-fluoro-7-methyl-14,15-methyleneestr-4-en-3-onea) and(7α,14β,15β,17β)-17-fluoro-17-(hydroxymethyl)-7-methyl-14,15-methyleneestra-4-en-3-one(b)

i)—A solution of(7α,14β,15β,17β)-3-methoxy-7-methyl-14,15-methylenespiroestra-1,3,5(10)-triene[17,2′]oxirane(Example 1, step iii; 1.75 g) in dry diethyl ether (43.7), cooled to−10° C., was treated with boron trifluoride diethyl etherate (1.75 ml).The reaction mixture was stirred for 15 min. and then quenched with asaturated aqueous solution of sodium hydrogencarbonate. The product wasextracted into ethyl acetate; the combined organic phases were washedwith a saturated aqueous solution of sodium hydrogencarbonate and brine,dried over sodium sulfate, and concentrated under reduced pressure.Column chromatography afforded(7α,14β,15β,17β)-17-fluoro-3-methoxy-7-methyl-14,15-methyleneestra-1,3,5(10)-triene-17-methanol(0.36 g).

ii)—Following a procedure analogous to that described under vi ofExample 1, the product obtained in the previous step (0.36 g) wasconverted to a mixture of(7α,14β,15β,17β)-17-fluoro-3-methoxy-7-methyl-14,15-methyleneestra-2,5(10)-diene-17-methanoland(7α,14β,15β,17α)-3-methoxy-7-methyl-14,15-methyleneestra-2,5(10)-diene-17-methanol(0.36 g, ratio 1:3).

iii)—Following a procedure analogous to that described under vii ofExample 1, the mixture of products obtained in the previous step (0.36g) was converted to(7α,14β,15β,17β)-17-fluoro-17-(hydroxymethyl-7-methyl-14,15-methyleneestr-4-en-3-oneand(7α,14β,15β,17α)-17-(hydroxymethyl)-7-methyl-14,15-methyleneestr-4-en-3-one(0.32 g, ratio 1:3).

iv)—A solution of the mixture obtained in the previous step (0.32 g) ina mixture of dry pyridine (1.50 ml) and dry tetrahydrofuran (5 ml),containing 4-(dimethylamino)pyridine (0.005 g) was treated with aceticanhydride (0.90 ml). The mixture was stirred at room temperature for 1.5h and then quenched with ice-water, followed by addition of a saturatedaqueous solution of sodium hydrogencarbonate. The product was extractedinto ethyl acetate; the combined organic phases were washed with water,aqueous sulfuric acid (2 M) and brine, dried over sodium sulfate, andconcentrated under reduced pressure. Column chromatography afforded(7α,14β,15β,17β)-17-[(acetyloxy)methyl]-17-fluoro-7-methyl-14,15-methyleneestr-4-en-3-one(0.050 g). ¹H NMR (CDCl₃) δ5.81 (bs, 1H), 4.22 (dd, part A of AB system,1H, J=22.8 and 12.2 Hz), 4.12 (dd, part B of AB system, 1H, J=22.4 and12.2 Hz), 2.10 (s, 3H), 1.17 (d, 3H, J=2.8 Hz), 0.62 (d, 3H, J=7.1 Hz).

v)—A solution of the product obtained under iv (0.030 g) in methanol (1ml) was treated with a solution of sodium hydroxide (0.009 g) in amixture of methanol (0.3 ml) and water (0.03 ml). The reaction mixturewas stirred at room temperature for 30 min. and poured into ice-water.The product was extracted into ethyl acetate; the combined organicphases were washed with brine, dried over sodium sulfate andconcentrated under reduced pressure, to give(7α,14β,15β,17β)-17-fluoro-17-(hydroxymethyl)-7-methyl-14,15-methyleneestr-4-en-3-one(0.030 g). ¹H NMR (CDCl₃) δ5.81 (bs, 1H), 3.74 (ddd, part A of ABsystem, 1H, J=20.4, 12.2 and 6.6 Hz), 3.60 (ddd, part B of AB system,1H, J=22.8, 12.2 and 6.7 Hz), 1.15 (d, 3H, J=2.8 Hz), 0.62 (d, 3H, J=7.1Hz); ¹⁹F NMR (CDCl₃) δ−156.08 (s).

EXAMPLE 10

(7α,14β,15β,17β)-17-[(Acetyloxy)methyl]-17-fluoro-7-methyl-14,15-methyleneestr-5(10)-en-3-one

i)—Following a procedure analogous to that described under Example 2,the mixture of(7α,14β,15β,17β)-17-fluoro-3-methoxy-7-methyl-14,15-methyleneestra-2,5(10)-diene-17-methanoland(7α,14β,15β,17β)-3-methoxy-7-methyl-14,15-methyleneestra-2,5(10)-diene-17-methanol(0.076 g, ratio 1:3) (Example 9, step ii) was converted to a mixture of(7α,14β,15β,17β)-17-fluoro-17-(hydroxymethyl)-7-methyl-14,15-methyleneestr-5(10)-oneand(7α,14β,15β,170β)-17-(hydroxymethyl)-7-methyl-14,15-methyleneestr-5(10)-en-3(0.060 g, ratio 1:3).

ii)—Following a procedure analogous to that described under iv ofExample 9, the mixture of products obtained under i (0.060 g) wasacetylated and separated by column chromatography, to give(7α,14β,15β,17β)-17-[(acetyloxy)methyl]-17-fluoro-7-methyl-14,15-methyleneestr-5(10)-en-3-one(0.008 g). ¹H NMR (CDCl₃) δ4.25 (dd, part A of AB system, 1H, J=23.6 and12.2 Hz), 4.12 (dd, part B of AB system, 1H, J=22.4 and 12.2 Hz), 2.73(bs, 2H), 2.09 (s, 3H), 1.12 (d, 3H, J=2.8 Hz), 0.69 (d, 3H, J=7.1 Hz).

EXAMPLE 11

(7α,14β,15β,17α,20S)-20-Hydroxy-7-methyl-14,15-methylene-19-norpregn-4-en-3-one(a) and(7α,14β,15β,17α,20R)-20-hydroxy-7-methyl-14,15-methylene-19-norpregn-4-en-3-one(b)

i)—A solution of(7α,14β,15β,17α)-3-methoxy-7-methyl-14,15-methyleneestra-1,3,5(10)-triene-17-carboxaldehyde(Example 1, step iv; 2.50 g) in dry tetrahydrofuran (15.4 ml), cooled to0° C., was treated with methylmagnesium chloride (1.5 M solution intetrahydrofuran, 62 ml). After 15 min. stirring, the reaction mixturewas quenched by addition of a saturated aqueous solution of ammoniumchloride. The product was extracted into ethyl acetate; the combinedorganic phases were washed with brine, dried over sodium sulfate andconcentrated under reduced pressure. Column chromatography afforded(7α,14β,15β,17α,20S)-3-methoxy-7-methyl-14,15-methylene-19-norpregna-1,3,5(10)-trien-20-ol(0.84 g) and(7α,14β,15β,17α,20R)-3-methoxy-7-methyl-14,15-methylene-19-norpregna-1,3,5(20-ol(0.23 g).

iia)—Following a procedure analogous to that described under vi ofExample 1,(7α,14β,15β,17α,20S)-3-methoxy-7-methyl-14,15-methylene-19-norpregna-1,3,5(20-ol(0.48 g) was converted to(7α,14β,15β,17α,20S)-3-methoxy-7-methyl-14,15-methylene-19-norpregna-2,5(10)-dien-20-ol(0.59 g).

iib)—Following a procedure analogous to that described under vi ofExample 1,(7α,14β,15β,17α,20R)-3-methoxy-7-methyl-14,15-methylene-19-norpregna-1,3,5(20-ol(0.23 g) was converted to(7α,14β,15β,17α,20R)-3-methoxy-7-methyl-14,15-methylene-19-norpregna-2,5(10)-dien-20-ol(0.11 g).

iiia)—Following a procedure analogous to that described under vii ofExample 1,(7α,14β,15β,17α,20S)-3-methoxy-7-methyl-14,15-methylene-19-norpregna-2,5(10)-dien-20-ol(0.59 g) was converted to(7α,14β,15β,17α,20S)-20-hydroxy-7-methyl-14,15-methylene-19-norpregn-4-en-3-one(0.33 g). ¹H NMR (CDCl₃) δ5.80 (m, 1H), 3.73 (m, 1H), 1.20 (s, 3H), 1.12(d, 3H, J=6.3 Hz), 0.62 (d, 3H, J=7.1 Hz), 0.44 (dd, 1H, J=7.9 and 5.1Hz), 0.26 (dd, 1H, J=5.1 and 3.1 Hz).

iiib)—Following a procedure analogous to that described under vii ofExample 1,(7α,14β,15β,17α,20R)-3-methoxy-7-methyl-14,15-methylene-19-norpregna-2,5(10)-dien-20-ol(0.11 g) was converted to(7α,14β,15β,17α,20R)-20-hydroxy-7-methyl-14,15-methylene-19-norpregn-4-en-3-one(0.060 g). ¹H NMR (CDCl₃) δ5.80 (m, 1H), 3.77 (m, 1H), 1.22 (d, 3H,J=6.7 Hz), 1.16 (s, 3H), 0.63 (d, 3H, J=7.1 Hz), 0.45 (dd, 1H, J=8.3 and5.1 Hz), 0.23 (dd, 1H, J=5.1 and 3.5 Hz).

EXAMPLE 12

(7α,14β,15β,17α)-20-Hydroxy-7,20-dimethyl-14,15-methylene-19-norpregn-4-en-3-one

i)—Following a procedure analogous to that described under ii of Example1, a mixture of(7α,14β,15β,17α,20S)-3-methoxy-7-methyl-14,15-methylene-19-norpregna-1,3,5(10)-trien-20-oland(7α,14β,15β,17α,20R)-3-methoxy-7-methyl-14,15-methylene-19-norpregna-1,3,5(10)-trien-20-ol(Example 11, step i; 0.45 g, ratio 1:1) was converted to(7α,14β,15β,17α)-3-methoxy-7-methyl-14,15-methylene-19-norpregna-1,3,5(10)-trien-20-one(0.55 g).

ii)—Following a procedure analogous to that described under i of Example11, the product obtained in the previous step (0.55 g) was converted to(7α,14β,15β,17α)-3-methoxy-7,20-dimethyl-14,15-methylene-19-norpregna-1,3,5(10)-trien-20-ol(0.26 g).

iii)—Following a procedure analogous to that described under vi ofExample 1, the product obtained in the previous step (0.14 g) wasconverted to(7α,14β,15β,17α)-3-methoxy-7,20-dimethyl-14,15-methylene-19-norpregna-2,5(10)-trien-20-ol(0.14 g).

iv)—Following a procedure analogous to that described under vii ofExample 1, the product obtained in the previous step (0.14 g) wasconverted to(7α,14β,15β,17α)-20-hydroxy-7,20-dimethyl-14,15-methylene-19-norpregn-4-en-3-one(0.050 g). ¹H NMR (CDCl₃) δ5.80 (m, 1H), 1.32 (s, 3H), 1.21 (s, 3H),1.20 (s, 3H), 0.64 (d, 3H, J=7.1 Hz), 0.42 (dd, 1H, J=7.9 and 5.1 Hz),0.25 (dd, 1H, J=5.1 and 3.5 Hz).

EXAMPLE 13

(7α,14β,15β,17α,20S)-17-(1-Hydroxypropyl)-17-methyl-14,15-methyleneestr-4-en-3-one

The title compound was prepared from(7α,14β,15β,17α)-3-methoxy-7-methyl-14,15-methyleneestra-1,3,5(10)-triene-17-carboxaldehyde(Example 1, step iv) using procedures described in Example 11. ¹H NMR(CDCl₃) δ5.80 (m, 1H), 3.75 (m, 1H), 1.21 (s, 3H), 0.93 (t, 3H, J=7.9Hz), 0.62 (d, 3H, J=7.1 Hz), 0.43 (m, 1H), 0.24 (m, 1H).

EXAMPLE 14

(7α,14β,15β,17α)-7-[(Acetyloxy)methyl)]-7-methyl-14,15-methyleneestr-4-en-3-one

A solution of(7α,14β,15β,17α)-17-(hydroxymethyl)-7-methyl-14,15-methyleneestr-4-en-3-one(Example 1, 0.20 g) in a mixture of dry pyridine (1.76 ml) and drytetrahydrofuran (8.8 ml) was treated with acetic anhydride (1.06 ml).The mixture was stirred at room temperature overnight and then quenchedwith water. After 1 h stirring the product was extracted into ethylacetate. The combined organic phases were washed with brine, dried oversodium sulfate, and concentrated under reduced pressure to give(7α,14β,15β,17α)17-[(acetyloxy)methyl)]-7-methyl-14,15-methyleneestr-4-en-3-one(0.22 g). ¹H NMR (CDCl₃) δ5.80 (t, 1H, J=2.8 Hz), 4.05 (dd, part A of ABsystem, 1H, J=11.0 and 6.3 Hz), 3.95 (dd, part B of AB system, 1H,J=11.0 and 7.1 Hz), 2.03 (s, 3H), 1.08 (s, 3H),. 0.62 (d, 3H, J=7.1 Hz),0.48 (dd, 1H, J=8.3 and 5.1 Hz), 0.27 (dd, 1H, J=5.1 and 3.5 Hz).

EXAMPLE 15

Following a procedure analogous to that described under v of Example 1,and using the compounds of Example 1, 2, and 8, respectively, asstarting material, the following products were prepared:

a)—(3β,7α,14β,15β,17α)-3-Hydroxy-7-methyl-14,15-methyleneestr-4-ene-17-methanol.

 ¹H NMR (CDCl₃) δ5.33 (bs, 1H), 4.21 (m, 1H), 3.67 (m, 1H), 3.48 (m,1H), 1.05 (s, 3H), 0.58 (d, 3H, J=7.1 Hz), 0.45 (dd, 1H, J=7.9 and 5.1Hz), 0.22 (dd, 1H, J=5.1 and 3.1 Hz).

b1)—(3α,7α,14β,15β,17α)-3-Hydroxy-7-methyl-14,15-methyleneestr-5(10)-ene-17-methanol.

 ¹H NMR (CDCl₃) δ4.09 (m, 1H), 3.69 (m, 1H), 3.50 (m, 1H), 1.03 (s, 3H),0.63 (d, 3H, J=7.1 Hz), 0.46 (dd, 1H, J=8.3 and 5.1 Hz), 0.24 (dd, 1H,J=5.1 and 3.5 Hz).

b2)—(3α,7α,14β,15β,17α)-3-Hydroxy-7-methyl-14,15-methyleneestr-5(10)-ene-17-methanol.

 ¹H NMR (CDCl₃) δ3.82 (m, 1H), 3.69 (m, 1H), 3.50 (m, 1H), 1.03 (s, 3H),0.63 (d, 3H, J=7.1 Hz), 0.46 (dd, 1H, J=8.3 and 5.1 Hz), 0.24 (dd, 1H,J=5.1 and 3.5 Hz).

c1)—(3β,7α,14β,15β,17β)-3,17-Dihydroxy-7-methyl-14,15-methyleneestr-4-ene-17methanol.

 ¹H NMR (CDCl₃) δ5.53 (m, 1H), 4.21 (m, 1H), 3.61 (dd, part A of ABsystem, 1H, J=10.6 and 4.7 Hz), 3.45 (dd, part B of AB system, 1H,J=10.6 and 5.9 Hz), 1.09 (s, 3H), 1.02 (dd, 1H, J=4.7 and 3.5 Hz), 0.56(d, 3H, J=7.1 Hz), 0.54 (dd, 1H, J=8.3 and 4.7 Hz).

c2)—(3α,7α,15β,17β)-3,17-Dihydroxy-7-methyl-14,15-methyleneestr-4-ene-17-methanol.

 ¹H NMR (CDCl₃) δ5.51 (m, 1H), 4.12 (m, 1H), 3.62 (dd, part A of ABsystem, 1H, J=10.6 and 4.7 Hz), 3.46 (dd, part B of AB system, 1H,J=10.6 and 5.9 Hz), 1.09 (s, 3H), 1.03 (dd, 1H, J=4.7 and 3.9 Hz), 0.59(d, 3H, J=7.1 Hz), 0.54 (dd, 1H, J=8.6 and 4.7 Hz).

EXAMPLE 16

(7α,14β,15β,17β)-17-Hydroxy-17-(methoxymethyl)-7-methyl-14,15-methyleneestr-4-en-3-one(reference compound 3)

i)—A solution of(7α,14β,15β,17β)-3-methoxy-7-methyl-14,15-methylenespiroestra-1,3,5(10)-triene[17,2′]oxirane(Example 1, step iii; 2.0 g) in dry methanol (106 ml) was treated withsodium methoxide (6.91 g) and refluxed overnight. The reaction mixturewas poured into ice-water and neutralized. The product was extractedinto diethyl ether; the combined organic phases were washed with asaturated aqueous solution of sodium hydrogencarbonate and brine, driedover sodium sulfate, and concentrated under reduced pressure. Columnchromatography gave(7α,14β,15β,17β)-3-methoxy-17-(methoxymethyl)-7-methyl-14,15-methyleneestra-1,3,5(10)-trien-17-ol(0.50 g).

ii)—Following a procedure analogous to that described under vi ofExample 1, the product obtained in the previous step (0.50 g) wasconverted to(7α,14β,15β,17β)-3-methoxy-17-(methoxymethyl)-7-methyl-14,15-methyleneestra-2,5(10)-dien-17-ol(0.69 g).

iii)—Following a procedure analogous to that described under vii ofExample 1, the product obtained in the previous step (0.69 g) wasconverted to(7α,14β,15β,17β)-17-hydroxy-17-(methoxymethyl)-7-methyl-14,15-methyleneestr-4-en-3-one(0.15 g). ¹H NMR (CDCl₃) δ5.80 (m, 1H), 3.42 (d, part A of AB system,1H, J=8.3 Hz), 3.33 (s, 3H), 3.16 (d, part B of AB system, 1H, J=8.3Hz), 1.11 (dd, 1H, J=4.7 and 3.5 Hz), 1.09 (s, 3H), 0.60 (d, 3H, J=7.1Hz), 0.50 (dd, 1H, J=8.3 and 4.7 Hz).

EXAMPLE 17

(7α,14β,15β,17β)-17-(Chloromethyl)-17-hydroxy-7-methyl-14,15-methyleneestr-4-en-3-one(reference compound 4)

i)—Following a procedure analogous to that described under vi of Example1,(7α,14β,15β)-3-methoxy-7-methyl-14,15-methyleneestra-1,3,5(10)-trien-17-one(Example 1, step ii; 8.0 g) was converted to(7α,14β,15β,17α)-3-methoxy-7-methyl-14,15-methyleneestra-2,5(10)-dien-17-ol(8.0 g).

ii)—Following a procedure analogous to that described under vii ofExample 1, the product obtained in the previous step (8.0 g) wasconverted to(7α,14β,15β,17α)-17-hydroxy-7-methyl-14,15-methyleneestr-4-en-3-one(2.51 g).

iii)—Following a procedure analogous to that described under ii ofExample 1, the product obtained in the previous step (2.51 g) wasconverted to (7α,14β,15β)-7-methyl-14,15-methyleneestr-4-ene-3,17-dione(2.23 g).

iv)—Boron trifluoride diethyl etherate (0.27 ml) was added to a mixtureof the product obtained in the previous step (2.23 g), 1,2-ethanedithiol(0.67 ml), dry tetrahydrofuran (10 ml), and dry methanol (20 ml), cooledto 0° C. After 2 h stirring at room temperature, the reaction mixturewas poured into water. The product was extracted into ethyl acetate; thecombined organic phases were washed with aqueous sodium hydroxide (10%)and brine, dried over sodium sulfate and concentrated under reducedpressure. Column chromatography gave(7α,14β,15β)-7-methyl-14,15-methyleneestr-4-ene-3,17-dione cyclic3-(1,2-ethanediyl dithioacetal) (2.68 g). The product was used in thenext step without further purification.

v)—Following a procedure analogous to that described under iii ofExample 1, the product obtained in the previous step (2.68 g) wasconverted to(7α,14β,15β,17β)-3-[(2-mercaptoethyl)thio]-7-methyl-14,15-methylenespiroestra-3,5-diene[17,2′]oxirane(2.81 g).

vi)—A solution of the product obtained in the previous step (0.50 g) indimethylformamide (7.3 ml) was treated with concentrated hydrochloricacid (0.73 ml). After 1 h stirring at room temperature, the reactionmixture was poured into a saturated aqueous solution of sodiumhydrogencarbonate and the product was extracted into ethyl acetate. Thecombined organic phases were washed with brine, dried over sodiumsulfate and concentrated under reduced pressure. Column chromatographyafforded(7α,14β,15β,17α)-17-(chloromethyl)-17-hydroxy-7-methyl-14,15-methyleneestr-4-en-3-one(0.035 g). ¹H NMR (CDCl₃) δ5.81 (m, 1H), 3.67 (d, part A of AB system,1H, J=11.0 Hz), 3.58 (d, part B of AB system, 1H, J=11.0 Hz), 1.17 (dd,1H, J=5.1 and 3.5 Hz), 1.15 (s, 3H), 0.60 (d, 3H, J=6.7 Hz), 0.54 (dd,1H, J=8.3 and 5.1 Hz).

EXAMPLE 18

Biological Results

The compounds according to the invention and four reference compoundswere tested for drogenic activity (the procedures for which have beendescribed above) and rated according the following scheme:

(−) no androgenic activity found: (+) androgenic activity found; (++)high androgenic activity; (+++) excellent androgenic activity; (n.d.) nodata available (pro) prodrug

I. Compounds of the Invention

Ex. R₁ R₂ R₃ R₄ R₅ R₆ R₇ R₈ R₉ R₁₀ R₁₁ Uns. Res.  1 oxo H Me H Me H H HH H H Δ⁴ +++  2 oxo H Me H Me H H H H H H Δ⁵⁽¹⁰⁾ +  3 oxo H Me H Me H HH H H H Δ^(4.9) ++  4 oxo Me Me H Me H H H H H H Δ⁴ ++  5 oxo H Et H MeH H H H H H Δ⁴ ++  6 oxo H Me H Et H H H H H H Δ⁴ +++  7 oxo H Me H Me H16β-Me H H H H Δ⁴ +  8 oxo H Me H Me H H OH H H H Δ⁴ +  9a oxo H Me H MeH H F H H Ac Δ⁴ ++  9b oxo H Me H Me H H F H H H Δ⁴ ++ 10 oxo H Me H MeH H F H H Ac Δ⁵⁽¹⁰⁾ + 11a oxo H Me H Me H H H 20S—Me H H Δ⁴ ++ 11b oxo HMe H Me H H H H 20R—Me H Δ⁴ + 12 oxo H Me H Me H H H Me Me H Δ⁴ + 13 oxoH Me H Me H H H 20S—Et H H Δ⁴ + 14 oxo H Me H Me H H H H H Ac Δ⁴ ++ 15a3β-OH H Me H Me H H H H H H Δ⁴ +++ 15b1 3β-OH H Me H Me H H H H H HΔ⁵⁽¹⁰⁾ pro 15b2 3α-OH H Me H Me H H H H H H Δ⁵⁽¹⁰⁾ Pro 15c1 3β-OH H Me HMe H H OH H H H Δ⁴ + 15c2 3α-OH H Me H Me H H OH H H H Δ⁴ +

II. Reference Compounds

Compound Result (14β,15β,17β)-17-hydroxy-17-(methoxymethyl)-14,15- —methyleneestr-4-en-3-one (reference compound 1, WO 99/67276, J 1222)(14β,15β,17β)-17-(chloromethyl)-17-hydroxy-14,15- —methyleneestr-4-en-3-one (reference compound 2, WO 99/67276, J 1364)(7α,14β,15β,17β)-17-hydroxy-17-(methoxymethyl)-7-methyl- —14,15-methyleneestr-4-en-3-one (reference compound 3, Example 16(7α,14β,15β,17β)-17-(chloromethyl)-17-hydroxy-7-methyl- —14,15-methyleneestr-4-en-3-one (reference compound 4, Example 17

What is claimed is:
 1. A compound satisfying the structural formula

wherein R₁ is O, (H,H), (H,OR), NOR, with R being hydrogen, (C₁₋₆)alkyl, (C₁₋₆) acyl; R₂ is hydrogen, or (C₁₋₆) alkyl; R₃ is hydrogen; orR₃ is (C₁₋₆) alkyl (C₂₋₆) alkenyl, or (C₂₋₆) alkynyl, each optionallysubstituted by halogen; R₄ is hydrogen, (C₁₋₆) alkyl, or (C₂₋₆) alkenyl;R₅ is (C₁₋₆) alkyl; R₆ is hydrogen, halogen, or (C₁₋₄) alkyl; R₇ ishydrogen, or (C₁₋₆) alkyl; R₈ is hydrogen, hydroxy, (C₁₋₆) alkoxy,halogen, or (C₁₋₆) alkyl; R₉ and R₁₀ are independently hydrogen; or R₉and R₁₀ are independently (C₁₋₆) alkyl, (C₂₋₆) alkenyl, (C₃₋₆)cycloalkyl, (C₅₋₆) cycloalkenyl, or (C₂₋₆) alkynyl, each optionallysubstituted by (C₁₋₄) alkoxy, or halogen; R₁₁ is hydrogen, SO₃H, (C₁₋₁₅)acyl; and the dotted lines indicate optional bonds, selected from a Δ⁴,Δ⁵⁽¹⁰⁾, or Δ¹¹ double bond, or a Δ^(4,9) or Δ^(4,11) diene system.
 2. Acompound according to claim 1, characterized in that the substituent R₁is O.
 3. A compound according to claim 1, wherein the dotted linesindicate a Δ⁴ double bond.
 4. A compound according to claim 1, whereinR₄ is 7α-methyl.
 5. the compound(7α,14β,15β,17α)-17-(hydroxymethyl)-7-methyl-14,15-methyleneestr-4-en-3-one.6. A pharmaceutical composition having androgenic activity comprising anefective amount of a compound according to claim 1 and apharmaceutically acceptable auxilary.
 7. A kit providing for hormonalcontraception in a male, comprising a sterilitant and an androgen,wherein the androgen is a compound according to claim
 1. 8. A method oftreatment for a human having androgen insufficiency comprisingadministering an effective amount of a compound according to claim
 1. 9.The method according to claim 8, wherein the human is a male, and theandrogen insufficiency is the result of the administration of asterilitant to said male in the course of a method of malecontraception.